Complementary and alternative therapies under the spotlight

LONDON — Complementary and alternative medicine remains the poor relation in the US biomedical community — a budget request of $113 million for fiscal year 2003 compared with $27 billion for the National Institutes of Health as a whole — but as neural imaging, molecular biology and clinical research begin to probe its secrets the promise of a brighter future for the field seems for the first time to be at least plausible.Yet the path to that future will not be straightforward, as findings presented at a special session on the subject at the American Association for the Advancement of Science (AAAS) in Boston this week showed. The placebo effect, for example, seems now to be more complex than previously thought, at least in the case of Parkinson's disease. And researchers have developed a model mechanism that explains why St John's Wort, taken as a herbal remedy for depression, interferes with the action of a certain drugs such as the immunosuppressant, cyclosporin, thus raising important questions about whether testing and labeling is appropriate for herbal remedies.The complexity of the placebo effect was graphically illustrated by Fabrizio Benedetti, a neurophysiologist from the University of Turin, in a short film of a man with Parkinson's disease. Benedetti's research, currently being prepared for publication, builds on work published last year in Science showing that placebos result in an increase in the neurotransmitter, dopamine, in Parkinson's patients. Dopamine is produced at lower concentrations in people with the disease, leading to poor motor control, such as shaky hand movements and unsteady gait.Knowing that the area in the brain (the caudate nucleus and putamen) that is damaged in patients with Parkinson's disease controls the excitability of another region affecting motor control (the subthalamic nucleus), Benedetti and his colleagues decided to explore what happens if they directly stimulate the subthalamic nucleus, and they surgically implanted electrodes in the brains of a number of patients.The film showed one patient's response when asked to move his hand between marks on a pad on a table in front of him in different circumstances. The patient's movements were slow and unsteady if he was told there was no stimulation. Yet unbeknownst to him, the subthalamic nucleus was being stimulated. By contrast when the patient was told that the region was being stimulated and was again asked to move his hand, his movements were steady and more rapid. The same physical intervention and effect in the brain, but a different verbal message and set of expectations, gave different results.As yet the research raises more questions than it answers. Further, the earlier work showing elevated dopamine production in response to placebo occurs in the same region as that damaged by Parkinson's. Why and how is it that the placebo response is so specific? Benedetti argues that exploring the biology in more detail is important, if physicians want to know how what patients are told, hear, see and smell affects their response to therapies, both conventional and alternative. His next step is to observe the biology and behavioral responses of Parkinson's patients at the level of a single neuron.As research into complementary and alternative medicines becomes more rigorous, a second area raising questions is that of herbal medicine. There is evidence, for example, that St John's Wort can ameliorate some types of depression, though the evidence is less clear cut that it seemed a few years ago (findings of a large multi-center clinical trial coordinated by Duke University are due to be published within a few weeks). Worryingly, though, St John's Wort can interfere with the action of other drugs. Given that sales of the herbal remedy in Europe in 1998 were $6 billion, and $140 million in the US, understanding the mechanism of this drug–drug interaction is a significant public health issue.Steve Kliewer, who is currently with GlaxoSmithKline at Research Triangle in North Carolina but is moving soon to the University of Texas Southwest Medical Center, described a mechanism his team has elucidated. They found that a constituent of St John's Wort can set a mechanism in motion that causes the body to eliminate drugs with certain structures from the body. Specifically, hyperflorin in the herb binds to a molecule that belongs to a class of nuclear receptors. Nuclear receptors mediate the activation of gene expression. In this case hyperflorin binds to PXR, which switches on a gene called XRE, which, in turn, produces a protein that oxidizes certain chemicals, making them more soluble so that they can be eliminated from the body. The whole system is the body's way of getting rid of unwanted and damaging molecules. Once the system is in motion, however, it does not know the good guys from the bad guys. The structural chemistry of some drugs — Kliewer estimates some 50% of those on the market — means they could fall victim to this process of elimination. St John's Wort, for example, lowers blood levels of HIV protease inhibitors.Additional testing and labels that warn of interactions with other drugs could nonetheless mean that St John's Wort can continue to be sold. That is, if clinical trials such as that about to be published from Duke University show that the remedy is indeed a better treatment than existing antidepressants.Findings such as those reported at the AAAS and the anticipated results of the clinical trial of effectiveness of St John's Wort in major depression represent the best quality work in complementary and alternative medicine, according to Stephen Strauss, director of the National Center for Complementary and Alternative Medicine (NCCAM), one of the National Institutes of Health. "Not all research in the area is yet of this quality," he told BioMed Central, "but it is what we are aiming for."NCCAM was formed in 1999 and this year has a budget of $104 million. The Center funds clinical trials, such as one jointly with the National Cancer Institute that is currently recruiting 1588 people to evaluate the effectiveness of shark cartilage as an adjuvant therapy for small cell lung cancer. Last year NCCAM also issued two requests for proposals to study basic neurobiological mechanisms. Speaking of this work, Strauss said, "The plural of anecdote is not evidence, we want to advance the evidence by looking rigorously at mechanisms and then conducting large trials."

Complementary and alternative therapies under the spotlight

Investigations into complementary and alternative medicine therapies presented at the AAAS throw up surprising results.

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